Neurotrophins are a family of factors that influence a multiplicity of functions in the central nervous system that range from supporting neuronal survival to eliciting apoptosis, regulating synaptic function, and influencing axonal growth. These distinct functions are mediated by the interactions of the factors with two distinct receptors, a member of the Trk family of receptor tyrosine kinases and the p75 neurotrophin receptor (NTR). It has recently been shown that neurotrophin precursors, proneurotrophins, selectively bind and activate p75NTR, effectively eliciting apoptosis, while the mature (cleaved) neurotrophins preferentially activate Trk signaling, which supports neuronal survival. Many neurons express Trk receptors and p75NTR, especially after injury when p75NTR is upregulated. In the proposed studies we will investigate how the signaling pathways activated by these different receptors interact to determine how neurons respond when exposed concomitantly to mature and proneurotrophins, as occurs after injury. Our previous studies have shown that p75NTR initiates apoptotic signaling while suppressing Trk-mediated survival signaling. Our proposed studies will explore these mechanisms further. One key determinant of whether Trk or p75NTR is activated depends on which form of the ligand, mature or proneurotrophins, are available to bind the different receptors. Since proneurotrophins can be secreted and cleaved extracellularly, we will investigate the regulation of proneurotrophin cleavage, particularly after seizures when we have detected increases in proneurotrophins in the CNS, and induction of p75NTR-mediated apoptosis. The p75NTR can function as a co-receptor with several other receptors to mediate different functions. The high-affinity binding of proneurotrophins to is due to the interaction with a co-receptor, sortilin, and our preliminary studies have shown that both receptors are required for proneurotrophins to elicit apoptosis. The signals that determine the association of p75NTR with its different co-receptors are unknown, and we will investigate this question in the proposed studies. In sum, these studies will provide greater insight into the multifunctional effects of neurotrophins in the brain, particularly under inflammatory conditions that occur after injury or in disease. PUBLIC HEALTH RELEVANCE: In these studies we will investigate the mechanisms by which neurotrophins regulate neuronal survival or death in the brain. We have previously determined that after seizures there is an increase in the p75 neurotrophin receptor that mediates neuronal cell death. Our studies will elucidate the mechanisms by which these key factors regulate neuronal death when the p75 receptor is induced, which occurs after different types of brain injury, as well as in neurodegenerative disease.